Various kinds of measurement are performed in clinical examinations or examinations in the biochemical field. At this time, the amount of a sample solution to be measured is often very small. Hence, there are proposed technologies such as micro TAS (Total Analysis Systems) and Lab on a Chip, in which measurement is conducted at high sensitivity by controlling the flow of a trace amount of liquid using a small chip.
In such technologies, a simple measurement method such as fluorometry, absorptiometry, electrochemical measurement, QCM (Quartz Crystal Microbalance) measurement, ATR (Attenuated Total Reflection) measurement, or SPR (Surface Plasmon Resonance) measurement is employed in many cases. In particular, the SPR measurement does not need specimen liquid labeling for detection, and can directly detect an antigen-antibody reaction or DNA combination and also simplify the measurement procedure (for example, see patent literatures 1 to 3 and non-patent literature 1). Additionally, in the SPR measurement, since the measurement area can be linear or planar, the flow velocity between two points can be measured by measuring the time difference in the refractive index change between the two points (for example, see patent literature 4).
In these measurement techniques, a sample cell capable of holding a sample solution is used. A trace amount of sample solution is supplied to the sample cell and fed, in the sample cell, to a detection portion that performs measurement. This makes it possible to conduct measurement at higher sensitivity and higher efficiency without lowering the concentration of a specimen such as DNA or an antibody dissolved or dispersed in the sample solution. The sample cell that feeds the sample solution to the detection portion is called a flow cell.
Various kinds of methods are proposed as methods of transferring a trace amount of sample solution in a flow cell. For example, there is a method of transferring a sample solution to a channel formed in a flow cell by applying a pressure from outside using a syringe pump or the like. There also exist a method of transferring a sample solution using an electrostatic force, an electrowetting method, a method of transferring a sample solution using a volume change or bubble generation by heating, and a method using an electroosmotic flow.
Also recently proposed is a method of transferring a sample solution by forming, in a flow cell, a region serving as a channel or pump capable of manifesting capillarity for the sample solution (for example, see patent literature 2). For this method, a flow cell is proposed in which a supply portion including an introduction port to introduce a sample solution, a transfer portion including a capillary pump that sucks the introduced sample solution, and a channel for measurement provided between the introduction port and the capillary pump are formed on a line along the planar direction of a plate-shaped flow cell. In this flow cell, when the sample solution is supplied to the introduction port, the sample solution enters from the introduction port and reaches the capillary pump via the channel. The sample solution is sucked by the capillary pump and continuously flows through the channel. There is also proposed a method of forming droplets of different radii at the two ends of a channel and transferring the liquid by the difference between the magnitudes of surface tensions generated on the droplets (for example, see non-patent literature 2).
The liquid feed method using the capillary force is called a passive pump because no external driving force is needed. A flow cell having the passive pump does not need a peripheral device for liquid feed and is therefore advantageous in on-site measurement such as point of care. Particularly, in the flow cell described in patent literature 1, a specimen liquid does not flow out of the flow cell. Hence, the biohazardous effect on the operator is small, and wastes associated with measurement can be reduced. In addition, one flow cell is used only once in measurement and then discarded. It is therefore possible to suppress measurement errors such as cross contamination.
Since a manufacturing method based on lithography is used, silicon, quartz, a glass wafer, or the like is used the material of the flow cell. As a bonding method for forming the flow cell, a method using heating and fusing, anodic bonding, bonding by hydrofluoric acid, or the like is used.
To cause the flow cell to function as a biosensor, a biomaterial is immobilized in the flow cell. However, the biomaterial has a low resistance to a high temperature, strong acid, strong alkali, and organic solvent. It is therefore difficult to make the flow cell function as a biosensor if it is manufactured using the above-described bonding method after the biomaterial is immobilized.
Studies have recently been conducted on using polydimethylsiloxane (to be referred to as “PDMS” hereinafter) as the material of a flow cell. This is because PDMS has a strong self-adhesive force to a glass or silicon substrate and does not need a bonding process, and a flow cell can easily be manufactured only placing the PDMS on the substrate. In addition, PDMS is hydrophobic because its contact angle to an aqueous solution is 90° or more. In liquid feed using the surface tension of a droplet, the hydrophobicity is advantageous in forming the droplet. However, to introduce a solution serving as priming water in advance, forcible liquid feed using a pipette or the like is needed as preconditioning. This is because even if the substrate that forms the channel is hydrophilic, the remaining surfaces are made of the hydrophobic PDMS, and an aqueous solution cannot be introduced without pressurization from outside.
As is apparent from this, it is difficult to implement, only by PDMS, the passive pump using the capillary force as the driving force. For this reason, a reagent is applied to the PDMS surface to attain hydrophilicity. However, the hydrophilicity is lost as time elapses. Studies have been conducted on adding a modifying agent to the PDMS itself to make the PDMS itself hydrophilic and manufacturing a flow cell for blood test (for example, see non-patent literature 3).
The above-described flow cell is of a disposable type aiming at easy measurement on site. On the other hand, there also exists a demand to collect many specimen liquids to an analysis center or the like and analyze an enormous number of specimens. In this case, the environment permits operators to use sufficient power, water, and drug solutions, and there are few constraints of the size of the measurement device. Hence, the measurement cost can be reduced by repetitive measurement in which instead of using a disposable flow cell, after a specimen liquid is fed to the channel, water or a cleaning fluid is subsequently fed to clean the channel, and the next specimen liquid is then fed.
To implement the repetitive measurement, there is proposed a flow cell including a supply portion with an introduction port to introduce a sample solution, a discharge portion with a delivery port to deliver the sample solution, and a channel for measurement provided between the supply portion and the discharge portion. In this flow cell, liquid feed is generally controlled by a pump (for example, see patent literatures 5 and 6). More specifically, a negative pressure is applied to the pump connected to the delivery port to suck a specimen liquid or cleaning fluid supplied to the supply portion, thereby feeding the liquid.
In a case in which repetitive measurement is performed using this flow cell, for example, if the negative pressure is continuously applied to completely suck the liquid in the channel or delivery portion, it is difficult to suck a liquid to be measured next that is supplied to the supply portion because a gas exists in the channel or delivery portion. In this case, priming water needs to be supplied to the flow cell to fill the channel or delivery portion with the liquid, resulting in an increase in time. In the repetitive measurement, the operation of the pump is controlled to attain a state in which the liquid stays in the channel and the delivery portion. For example, the pump is stopped when the liquid in the introduction portion completely flows to the channel, thereby attaining the state in which the liquid stays in the channel and the delivery portion.
Such repetitive measurement is effective in, for example, blood coagulation measurement. In recent years, life-style related diseases caused by a Western dietary life, lack of exercise, accumulation of stress, the progress of aging, and the like have become a serial social problem. An example of a disease caused by the life-style related diseases is a thrombosis. The thrombosis is strongly correlated with a myocardial infarction. Hence, it will be more important to do blood coagulation measurement in a periodic blood test in the future.